Case Presentation: A 26-year-old male with depression and anxiety on fluoxetine 30 mg daily and daily cannabis use was admitted to the ED for intractable vomiting and was presumed to have cannabinoid hyperemesis syndrome (CHS), consistent with multiple prior admissions. On arrival his vitals included BP 151/98, HR 98, RR 20, Temp 97.3F, and SpO2 99% on room air. He was again observed to have recurrent paroxysmal tachycardia into the 140–150s, a pattern noted on previous visits. The primary team performed a focused neurologic examination revealing rotary nystagmus, hyperreflexia, rigidity, and inducible ankle and jaw clonus. Laboratory evaluation showed leukocytosis (31.7 ×10⁹/L), hypokalemia (3.2), lactic acidosis (13.6), and elevated CPK (616). The patient had received haloperidol and lorazepam in the ED for agitation. Urine toxicology was negative for cocaine and amphetamines and he denied alcohol use. Serotonin syndrome (SS) was diagnosed using Hunter’s criteria in the setting of fluoxetine therapy, which has been documented to precipitate SS even as monotherapy. Fluoxetine was discontinued, and symptoms resolved within 24 hours; the remainder of his hospital course was uncomplicated.
Discussion: Serotonin syndrome is an iatrogenic toxidrome caused by excess serotonergic activity predominantly at 5-HT2A receptors, producing the triad of neuromuscular excitation, autonomic instability, and altered mental status. Diagnosis is clinical using the Hunter’s criteria. Early SS may resemble CHS, a far more common cause of nausea and vomiting. Although CHS is widely encountered in hospital medicine, presentations that include agitation, paroxysmal tachycardia, or neuromuscular hyperactivity introduce diagnostic instability that hospitalists should be prepared to evaluate. SS remains widely underreported and is often considered only in the setting of polypharmacy; nonetheless, emerging literature demonstrates that fluoxetine’s long half-life and active metabolites can, although rarely, precipitate SS even as monotherapy. This creates an important clinical overlap with CHS, as both conditions may feature vomiting, diaphoresis, anxiety, and autonomic changes. Despite its prevalence, neuromuscular findings such as clonus, hyperreflexia, or nystagmus are rarely scrutinized in patients presenting with intractable vomiting, leading to a major diagnostic blind spot for hospitalists. This oversight is further compounded by the routine use of haloperidol and metoclopramide in CHS management, both of which can exacerbate serotonergic toxicity, creating a cycle of worsening symptoms that appear to reinforce the incorrect diagnosis. The hospital medicine community increasingly recognizes the benefit of integrating neuromuscular examination into the assessment of severe nausea/vomiting, particularly when symptoms appear inconsistent with the expected CHS trajectory. Other conditions to keep in mind that can also closely mirror SS include cocaine and amphetamine toxicity as well as severe alcohol withdrawal. Urine toxicology may assist in distinguishing these conditions. Recognizing these overlapping symptom clusters and the cognitive tendency to anchor on a familiar diagnosis may help hospitalists avoid premature closure and broaden their evaluation in such cases.
Conclusions: Clinicians should maintain a wide differential and consider SS in patients on SSRIs who present with agitation and multisystem symptoms.